EP1861092A4 - Ouvreur des canaux potassiques à squelette benzofuroindole - Google Patents

Ouvreur des canaux potassiques à squelette benzofuroindole

Info

Publication number
EP1861092A4
EP1861092A4 EP06716305A EP06716305A EP1861092A4 EP 1861092 A4 EP1861092 A4 EP 1861092A4 EP 06716305 A EP06716305 A EP 06716305A EP 06716305 A EP06716305 A EP 06716305A EP 1861092 A4 EP1861092 A4 EP 1861092A4
Authority
EP
European Patent Office
Prior art keywords
hydrogen
compound
cooh
channel
benzofuroindole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP06716305A
Other languages
German (de)
English (en)
Other versions
EP1861092A1 (fr
EP1861092B1 (fr
Inventor
Yong-Chul Kim
Chul-Seung Park
Tal-Soo Ha
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Anygen Co Ltd
Original Assignee
Anygen Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Anygen Co Ltd filed Critical Anygen Co Ltd
Publication of EP1861092A1 publication Critical patent/EP1861092A1/fr
Publication of EP1861092A4 publication Critical patent/EP1861092A4/fr
Application granted granted Critical
Publication of EP1861092B1 publication Critical patent/EP1861092B1/fr
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47G—HOUSEHOLD OR TABLE EQUIPMENT
    • A47G19/00—Table service
    • A47G19/22—Drinking vessels or saucers used for table service
    • A47G19/2205—Drinking glasses or vessels
    • A47G19/2227—Drinking glasses or vessels with means for amusing or giving information to the user
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47G—HOUSEHOLD OR TABLE EQUIPMENT
    • A47G19/00—Table service
    • A47G19/22—Drinking vessels or saucers used for table service
    • A47G19/2205—Drinking glasses or vessels
    • A47G19/2227—Drinking glasses or vessels with means for amusing or giving information to the user
    • A47G2019/2238—Drinking glasses or vessels with means for amusing or giving information to the user with illumination means
    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47G—HOUSEHOLD OR TABLE EQUIPMENT
    • A47G2200/00—Details not otherwise provided for in A47G
    • A47G2200/08—Illumination

Definitions

  • the present invention relates to a potassium channel opener having benzofuroindole skeleton. More particularly, this invention relates to a novel potassium channel opener having benzofuroindole skeleton which can be produced by substituting the substituent radicals and its preparation method.
  • Potassium channels belong to a ubiquitous and heterogeneous protein family, selectively permitting K + ions to move across the cell membrane. These channels play an important role in adjusting cellular excitability through maintenance of the optimum set of conditions for K + ion and its various effects on membrane potential and membrane resistance.
  • K channel in human body which are activated by different mechanism.
  • calcium-activated potassium channels are the one, of which opening was determined by the raise of the intracellular calcium concentrations, and regulated by transmenbrane voltage and phosphorylation states. Calcium-activated potassium channels are further divided into three major types, which can be distinguished electropysiologically by their different single-channel conductance.
  • the BKca (or Maxi-K) channel has the particular function of large single-channel conductance (100—250 pS), whereas other two major types of calcium dependent potassium channels are small conductance 92—25 pS, SKca) and intermediate conductance group (25—100 pS, IKc 3 ).
  • BKca channel is particularly regarded because of the extensive K + efflux and membrane hyperpolarization due to their large single-channel conductance, and their expression in a range of non-excitable and excitable cell types including neurons and muscles.
  • BKca channels play roles in shaping action potentials and regulating neuronal excitability and neurotransmitter release in nervous system.
  • BKca channel activators or openers designed chemical openers of BKca channel would be a strategy for the development of drugs to treat neuronal damages resulted from traumatic and ischemic events or neuro-degenerative processes.
  • BKca channels are composed of two different subunits: the pore forming a subunit and the auxiliary ⁇ subunits. Although channels formed only by four a subunits can be functional, ⁇ subunits alter the biophysical and pharmacological properties of homomeric channels, including Ca 2+ and voltage sensitivity, and gating kinetics.
  • BKca channel openers e.g., dehydrosoyasaponin-I, maxikdiol, NS-1619, BMS-204352, 17- ⁇ -estradiol, ethylbromide tamoxifen, pimaric acid and epoxyeicosatrienoic acid.
  • some synthetic activators such as, NS-1619 and BMS-204352, act on the a subunit
  • other openers of BK Ca channels including dehydrosoyasaponin-I and 17- ⁇ -estradiol, require ⁇ subunit for their action.
  • activators derived from natural products such as dehydrosoyasaponin-I are impermeable to the cell membrane and act only on intracellular side of BKca channels.
  • BMS-204352 prototypical BKca channel openers 1 (BMS-204352), quinolinone analog 2 and substituted benzofuroindole analog 3, compound 1 was reported to selectively shift the BKca channel activation curve toward less positive membrane potentials in a dose dependent manner and currently in clinical trials targeting acute ischemic stroke.
  • Benzofuroindole analog 3 was studied as a BKca channel opener to show bladder selective smooth muscle relaxation effect and increasing outward current in voltage clamp experiment on isolated rat bladder smooth muscle cells.
  • no further results have been reported regarding the structural activity or biological property in the duplicated BKca channel.
  • the object of the present invention is to provide a potassium channel opener having benzofuroindole skeleton representing the following formula ( I ).
  • R 1 is hydrogen
  • R 2 is CF3
  • R3 is COOH
  • R4 is hydrogen
  • R5 is hydrogen or chloride
  • R 6 is hydrogen or chloride.
  • the present invention provide a compound wherein it comprises that R 1 is hydrogen, R 2 is CF3, R3 is COOH, R4 is hydrogen, R5 is hydrogen and R 6 is hydrogen; a compound wherein it comprises that Ri is hydrogen, R 2 is CF3, R3 is COOH, R 4 is hydrogen, R5 is hydrogen and R 6 is chloride; a compound wherein it comprises that R 1 is hydrogen, R 2 is CF3, R3 is COOH, R 4 is hydrogen, R5 is chloride and R 6 is hydrogen.
  • the present invention provide a process for preparing a potassium channel opener having benzofuroindole skeleton representing the following formula ( I ), which comprises the steps of : i ) preparing compound of formula (IE) by reacting and condensing salicylic acid derivatives represented by formula ( ⁇ ) as starting material
  • Ri is 4-CF 3 , 4-H, R 2 is 1-COOH, 1-Cl, 3-Cl, 4-Cl.
  • FIG. 1 illustrates chemical structures of BKca channel openers of present invention.
  • FIG. 2 illustrates a superimposed structure of benzofuroindole compound of present invention and BMS-2043552.
  • FIG. 3 illustrates relative fold-increase of BKca channel activity by extracellularly applied benzofuroindole analogues of present invention. Bar graphs represent fold increases in BKca channel currents evoked by extracellular treatment of various compounds at 20 ⁇ M.
  • FIG. 4 illustrates potency of extracellularly applied compound 22 on rSlo channels in various intracellular Ca concentrations.
  • Intracellular Ca concentration was increased from Ca 2+ -free (A), 0.5 ⁇ M (B), l ⁇ M (C) and 2 ⁇ M (D).
  • the concentration of compound 22 was 20 ⁇ M on the extracellular side.
  • FIG. 6 illustrates concentration-dependence activity of compound 8 on BKca channel.
  • FIG. 6A illustrates concentration-dependence activity of rSlo channel.
  • FIG. 6B illustrates concentration-dependence activity of rSlo channel combined with human ⁇ l.
  • FIG. 6C illustrates concentration-dependence activity of rSlo channel combined with rat /34 subunit.
  • Trifluoromethyl and chloro groups were accordingly selected for the substitution at 7 and 4 positions of benzofuroindole template, respectively. Also, synthesis of other benzofuroindole series with different functional groups were included as briefly depicted in Scheme 1 to determine the structure activity relationships.
  • R 2 1-COOH, Cl, CF 3 2-CF 3 , 3-CF 3 , 4-CI
  • Salicylic esters obtained from Fisher esterification of commercially available substituted salicylic acids were alkylated with ethylbromoacetate and subsequent double-branch hydrolysis gave 5a— e.
  • the benzofuranones were couple wih various substituted phenylhydrazines to afford corresponding hydrazones, which were subjected to Fisher-indole reaction to convert into benzofuroindole derivatives, 7 — 23 in reflux condition or microwave reaction with acid catalysts.
  • Table 1 shows the various benzofuroindole derivatives obtained according to above method.
  • the advantageous effect of the present invention is to provide a potassium channel opener having benzofuroindole skeleton.
  • the inventors report an optimization of the pharmacophores in benzofuroindole skeleton for BKca channel opening activity from the synthesis of a series of substituted benzofuroindole derivatives and the electrophysiological property with Ca 2+ independent manner.
  • Example 2 Measuring the activity of compound of the present invention on cloned vector BKca (rSlo) channel
  • Excised outside-out patch configurations were obtained by making a gigaohm seal, rupturing the membrane pulling the pipette from oocytes. Both of the bath and pipette contained symmetrical 124 mM K + ions. Voltage pulses were applied to activate rSlo channel currents from -120 mV to 140 mV in 10 mV increments and intracellular Ca 2+ concentrations were used to activate rSlo channel from 0 (Ca 2+ -free solution was to chelate with 5 mM EGTA) to 2 ⁇ M in intracellular side.
  • FIG. 4 shows markedly induced rSlo channel currents by extracellularly applied compound 22 and it is recovered after the washout in tested entire concentrations of intracellular Ca .
  • the neuronal BKca channels can be activated by compound 22 even at the resting membrane potentials of about -60 ⁇ -80 mV in the presence of marginal free Ca 2+ concentration of under 100 nM.
  • benzofuroindole skeleton was compared with a known BKca channel opener, BMS-204352, to optimizer pharmacophore groups to be incorporated.
  • BMS-204352 a known BKca channel opener
  • compound 22 was identified as the potent and effective BKca channel openers with intracellular calcium independent manner.
  • the BKca channel opener might be further applied to the therapeutic interventions in stroke, asthma, hypertension, convulsion and traumatic brain injury.
  • the intracellular Ca 2+ concentration was fixed at 2 ⁇ M to activate rSlo channels, and different concentrations of compound 8 were added to the intracellular side of the membrane. Although intracellular compound 8 also increased rSlo currents with a similar apparent affinity, its-fold increase was much smaller than that obtained from extracellular side.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Furan Compounds (AREA)
EP06716305A 2005-03-10 2006-03-10 Ouvreur des canaux potassiques à squelette benzofuroindole Not-in-force EP1861092B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020050020008A KR100659498B1 (ko) 2005-03-10 2005-03-10 벤조퓨로인돌계 칼륨 채널 개시제
PCT/KR2006/000855 WO2006096030A1 (fr) 2005-03-10 2006-03-10 Ouvreur des canaux potassiques à squelette benzofuroindole

Publications (3)

Publication Number Publication Date
EP1861092A1 EP1861092A1 (fr) 2007-12-05
EP1861092A4 true EP1861092A4 (fr) 2009-04-15
EP1861092B1 EP1861092B1 (fr) 2010-09-15

Family

ID=36953595

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06716305A Not-in-force EP1861092B1 (fr) 2005-03-10 2006-03-10 Ouvreur des canaux potassiques à squelette benzofuroindole

Country Status (8)

Country Link
US (1) US7812177B2 (fr)
EP (1) EP1861092B1 (fr)
JP (1) JP5053989B2 (fr)
KR (1) KR100659498B1 (fr)
CN (1) CN101137361B (fr)
AT (1) ATE481098T1 (fr)
DE (1) DE602006016922D1 (fr)
WO (1) WO2006096030A1 (fr)

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US8260393B2 (en) 2003-07-25 2012-09-04 Dexcom, Inc. Systems and methods for replacing signal data artifacts in a glucose sensor data stream
US8010174B2 (en) 2003-08-22 2011-08-30 Dexcom, Inc. Systems and methods for replacing signal artifacts in a glucose sensor data stream
US7778680B2 (en) 2003-08-01 2010-08-17 Dexcom, Inc. System and methods for processing analyte sensor data
US7591801B2 (en) 2004-02-26 2009-09-22 Dexcom, Inc. Integrated delivery device for continuous glucose sensor
US8845536B2 (en) 2003-08-01 2014-09-30 Dexcom, Inc. Transcutaneous analyte sensor
US20190357827A1 (en) 2003-08-01 2019-11-28 Dexcom, Inc. Analyte sensor
US8275437B2 (en) 2003-08-01 2012-09-25 Dexcom, Inc. Transcutaneous analyte sensor
US20140121989A1 (en) 2003-08-22 2014-05-01 Dexcom, Inc. Systems and methods for processing analyte sensor data
US7920906B2 (en) 2005-03-10 2011-04-05 Dexcom, Inc. System and methods for processing analyte sensor data for sensor calibration
WO2005051170A2 (fr) 2003-11-19 2005-06-09 Dexcom, Inc. Recepteur integre pour capteur d'analyte en continu
US9247900B2 (en) 2004-07-13 2016-02-02 Dexcom, Inc. Analyte sensor
US8532730B2 (en) 2006-10-04 2013-09-10 Dexcom, Inc. Analyte sensor
US8364231B2 (en) 2006-10-04 2013-01-29 Dexcom, Inc. Analyte sensor
EP3263032B1 (fr) 2003-12-09 2024-01-24 Dexcom, Inc. Traitement de signal pour capteur d'analyte continu
US8808228B2 (en) 2004-02-26 2014-08-19 Dexcom, Inc. Integrated medicament delivery device for use with continuous analyte sensor
US8170803B2 (en) 2004-07-13 2012-05-01 Dexcom, Inc. Transcutaneous analyte sensor
US7783333B2 (en) 2004-07-13 2010-08-24 Dexcom, Inc. Transcutaneous medical device with variable stiffness
US7905833B2 (en) 2004-07-13 2011-03-15 Dexcom, Inc. Transcutaneous analyte sensor
US20080306434A1 (en) 2007-06-08 2008-12-11 Dexcom, Inc. Integrated medicament delivery device for use with continuous analyte sensor
EP4159114B1 (fr) 2007-10-09 2024-04-10 DexCom, Inc. Système d'administration d'insuline intégré avec un capteur de glucose en continu
US8290559B2 (en) 2007-12-17 2012-10-16 Dexcom, Inc. Systems and methods for processing sensor data
CA2715628A1 (fr) 2008-02-21 2009-08-27 Dexcom, Inc. Systemes et procedes pour traiter, transmettre et afficher des donnees de detecteur
US8396528B2 (en) 2008-03-25 2013-03-12 Dexcom, Inc. Analyte sensor
US9848809B2 (en) 2011-04-15 2017-12-26 Dexcom, Inc. Advanced analyte sensor calibration and error detection
CN106632360A (zh) * 2016-09-27 2017-05-10 上海道亦化工科技有限公司 基于苯并呋喃并吲哚的化合物及其有机电致发光器件
US20190117131A1 (en) 2017-10-24 2019-04-25 Dexcom, Inc. Pre-connected analyte sensors
US11331022B2 (en) 2017-10-24 2022-05-17 Dexcom, Inc. Pre-connected analyte sensors

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WO2000034285A2 (fr) * 1998-12-04 2000-06-15 American Home Products Corporation Indenoindoles et benzofuranoindoles substitues utilises comme nouveaux elements d'ouverture de canaux potassiques
WO2004099191A2 (fr) * 2003-05-02 2004-11-18 Wyeth Quinolines benzofuranyl et benzothienyl-piperazinyl et leurs procedes d'utilisation

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Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2000034285A2 (fr) * 1998-12-04 2000-06-15 American Home Products Corporation Indenoindoles et benzofuranoindoles substitues utilises comme nouveaux elements d'ouverture de canaux potassiques
WO2004099191A2 (fr) * 2003-05-02 2004-11-18 Wyeth Quinolines benzofuranyl et benzothienyl-piperazinyl et leurs procedes d'utilisation

Non-Patent Citations (3)

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Title
BUTERA JOHN A ET AL: "Synthesis and potassium channel opening activity of substituted 10H-benzo(4,5)furo(3,2-b)indole- and 5,10-dihydro-indeno(1,2-b)indole 1-carboxylic acids", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 11, no. 16, 20 August 2001 (2001-08-20), pages 2093 - 2097, XP009101112, ISSN: 0960-894X *
GORMEMIS AHMET E ET AL: "Benzofuroindole analogues as potent BK(Ca) channel openers.", CHEMBIOCHEM : A EUROPEAN JOURNAL OF CHEMICAL BIOLOGY OCT 2005, vol. 6, no. 10, October 2005 (2005-10-01), pages 1745 - 1748, XP002482857, ISSN: 1439-4227 *
NARDI ANTONIO ET AL: "Natural modulators of large-conductance calcium-activated potassium channels.", PLANTA MEDICA, vol. 69, no. 10, October 2003 (2003-10-01), pages 885 - 892, XP002482856, ISSN: 0032-0943 *

Also Published As

Publication number Publication date
KR20050032080A (ko) 2005-04-06
WO2006096030A1 (fr) 2006-09-14
ATE481098T1 (de) 2010-10-15
EP1861092A1 (fr) 2007-12-05
JP5053989B2 (ja) 2012-10-24
DE602006016922D1 (de) 2010-10-28
KR100659498B1 (ko) 2006-12-20
EP1861092B1 (fr) 2010-09-15
CN101137361A (zh) 2008-03-05
US20080194837A1 (en) 2008-08-14
JP2008533001A (ja) 2008-08-21
US7812177B2 (en) 2010-10-12
CN101137361B (zh) 2010-11-24

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